ES2857815T3 - Methods of use of fermented formula for infants - Google Patents

Abstract

Non-therapeutic method to promote improved self-regulation of energy intake in an infant, wherein said method comprises administering a nutritional composition that is an infant formula comprising 3 to 7 g of lipids / 100 kcal, 1.25 to 5 g of protein / 100 kcal and 6 to 16 g of digestible carbohydrate / 100 kcal and where the nutritional composition comprises an ingredient fermented by lactic acid producing bacteria, and from 0.05 to 1.5% by weight of acid lactic acid based on dry weight and where the nutritional composition comprises from 0.25% by weight to 20% by weight of indigestible oligosaccharides based on the dry weight of the nutritional composition, where the nutritional composition is administered to an infant with an age below 6 months, more preferably below 4 months of age and improved self-regulation of energy intake is compared to self-regulation of energy intake of pre-fed infants Infant grade that does not comprise an ingredient fermented by lactic acid producing bacteria, and 0.05 to 1.5% by weight of lactic acid based on dry weight.

Description

DESCRIPTION

Methods of use of fermented formula for infants

FIELD OF THE INVENTION

[0001] The invention relates to an infant food, in particular an infant formula.

BACKGROUND OF THE INVENTION

[0002] Human milk is the undisputed gold standard of infant nutrition. However, in some cases breastfeeding is inadequate or unsuccessful for medical reasons or because of the choice not to breastfeed. Infant or follow-up formulas have been developed for such situations. Commercial infant formulas are now commonly used to provide a complementary or unique food source in the first few years of life. These formulas comprise a range of nutrients to meet the nutritional needs of the growing infant and typically include fat, carbohydrates, protein, vitamins, minerals, and other nutrients useful for optimal infant growth and development. Commercial infant formulas are designed to mimic, as closely as possible, the composition and function of human milk.

[0003] It has long been observed that breastfed infants have a different pattern or trajectory of weight gain compared to formula-fed infants. Numerous studies conducted in various regions around the world have reported that breastfed infants have slower weight gain. Length gain tends to differ less between breastfed and formula-fed infants, and as a result, breastfed infants are leaner. Thus, it has been reported in the art that the growth curve of infants fed commercial infant formula differs from the growth curve of breastfed infants. Typically, an infant formula has a growth (weight) accelerating effect in the first year of life. Furthermore, this difference in growth trajectories is correlated with a higher body mass index in early life and a higher risk of developing obesity later in life. Li et al, 2010, Pediatrics 125: e1386-e1393 reveal that infants who are bottle-fed in early infancy are more likely to finish the bottle or cup in late infancy than those who are directly breastfed. Bottle feeding, regardless of the type of milk, differs from feeding directly from the breast in its effect on self-regulation of children's milk intake.

[0004] In the state of the art in the field of infant formula to improve the growth trajectory to be more similar to the growth trajectory of breastfed infants, the focus is on an infant formula with less protein and / or lower caloric density. WO 2008/071667 discloses a nutritional composition for infants at risk of developing obesity later in life comprising a protein source, a lipid source and a carbohydrate source. The protein content is less than 1.8 g / 100 kcal and the energy density is less than 650 kcal / liter. In WO 2010/070613 it is disclosed that a lower weight gain was observed in the first week of life when using a preparation with a very low calorie content and a low protein content based on volume. Koletzko et al, 2009, Am J Clin Nutr 89: 1836-1845 reveal that the use of an isocaloric infant formula and follow-on with a protein content of 1.77 and 2.1 g / 100 kcal resulted in a lower weight gain than in the group of infants who consumed an infant formula or follow-on with a high protein concentration of 2.9 and 4.4 g / 100 kcal. At 24 months, the weight-for-length z-score of infants in the lower-protein formula group was lower than that of the high-protein group and did not differ from that of the breastfed control group. In WO 2015/078505 a lower weight gain is observed in the period of 3 to 6 months when a preparation comprising a lower protein content is administered than in the control. WO 2015/091789 focuses on oligosaccharide mixtures comprising N-acetylated oligosaccharide, galactooligosaccharide and / or sialylated oligosaccharide that promote a growth rate that approximates the growth rate of breastfed infants. WO 2012/1078039 refers to fermented infant formula to reduce the digestive effort of proteins by reducing the amount of endogenously formed proteases, concomitant with an increase in protein digestion. Improved digestion allows protein levels to be reduced. WO 2012/1078039 also refers to low protein fermented infant formula. US 2014/0162223 provides methods to prevent and / or reduce early childhood obesity that can help instill early healthy eating habits and preferences for nutritious foods in infants and young children, promote an appropriate early growth trajectory and weight status. long-term that is consistent with public policy recommendations and is associated with long-term health. WO 2013/187764 discloses fermented infant formulas comprising indigestible oligosaccharides to improve the health of the intestinal tract by reducing the digestive effort of proteins. WO 2015/065194 discloses a fermented infant or follow-on preparation comprising indigestible oligosaccharides to decrease the duration of crying, reduce crying spells and the incidence of colic in infants.

SUMMARY OF THE INVENTION

[0005] An efficacy study on the growth and safety of a partially fermented infant formula during a 3-4 month intervention was investigated in healthy term born infants compared to a standard formula and a breastfed control. In a prospective, randomized, controlled, double-blind, multicenter clinical trial, infants were enrolled before 28 days of age and assigned to receive one of two formula until 17 weeks of age: 1) an infant formula comprising a fermented formula, or 2 ) an unfermented infant formula. The composition of the preparations was similar in energy and macronutrient composition. As a reference, we included a group of infants who were exclusively breastfed until 17 weeks of age. Growth was evaluated by equivalence analysis of daily weight gain and daily BMI increase during the intervention period using equivalence margins of ± 0.5 SD, between the preparation groups as well as in comparison with the group. breastfed referral. The length was also monitored monthly.

[0006] At 17 weeks statistically significant greater weight gain and BMI increase was observed for the control group, compared to the breastfed control group. There was no statistically significant difference in weight gain or increase in BMI in the infants fed the fermented formula compared to the control breastfed group, or compared to the infants fed the control formula.

[0007] At 17 weeks of age, significant differences in eating behaviors were observed, in particular a response to increased satiety, a decreased response to food and a decreased general appetite was observed in the group that received the fermented preparation. This is indicative of the improvement of the infant's self-regulation of energy intake towards the self-regulation of energy intake observed in breastfed infants.

[0008] Both the effect observed in growth trajectories early in life, which are more similar to the breastfed reference group, and that observed in eating behavior are indicative of a lower risk of being overweight or obese later in life. life in infants consuming a fermented preparation.

[0009] While in the art it is normally considered that too high a protein intake during childhood is a risk factor for overweight and / or obesity and therefore it is considered beneficial to reduce the level of protein in a preparation for infants, surprisingly the present inventors found that the inclusion of a fermented ingredient in the low protein infant food independently improved the effects on feeding behavior and growth trajectory and thus improves the effect on the prevention of overweight and / or obesity .

DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention, therefore, concerns a non-therapeutic method for promoting improved self-regulation of energy intake in an infant, wherein said method comprises administering a composition which is an infant formula comprising 3 to 7 g of lipids / 100 kcal, 1.25 to 5 g of protein / 100 kcal and 6 to 16 g of digestible carbohydrate / 100 kcal and where the nutritional composition comprises an ingredient fermented by lactic acid producing bacteria, and a 0.05 to 1.5% by weight of lactic acid based on dry weight and where the nutritional composition comprises 0.25% by weight to 20% by weight of non-digestible oligosaccharides based on dry weight of the nutritional composition, where the nutritional composition is administered to an infant less than 6 months of age, more preferably less than 4 months of age, and the improved self-regulation of energy intake is compared to the self-regulation of energy intake in l Actives fed infant formula not comprising an ingredient fermented by lactic acid producing bacteria and 0.05 to 1.5% by weight of lactic acid based on dry weight.

[0011] In another embodiment, the present invention relates to a non-therapeutic method for promoting improved eating behavior in a child, wherein the improved eating behavior is selected from the group consisting of slower eating, a increased responsiveness to satiety, decreased responsiveness to food, optimal food enjoyment and optimal appetite, more preferably increased responsiveness to satiety, decreased responsiveness to food, and a decrease in general appetite, where said method comprises administering a nutritional composition that is an infant formula comprising 3 to 7 g of lipids / 100 kcal, 1.25 to 5 g of protein / 100 kcal and 6 to 16 g of digestible carbohydrate / 100 kcal and where the nutritional composition comprises an ingredient fermented by lactic acid producing bacteria, and from 0.05 to 1.5% by weight of lactic acid based on dry weight, and wherein the nutritional composition comprises from 0.25% by weight to 20% by weight of nondigestible oligosaccharides based on the dry weight of the nutritional composition, wherein the nutritional composition is administered at a infant with an age less than 6 months, more preferably less than 4 months of age and the improved feeding behavior is compared with the speed of ingestion, the response to satiety; responsiveness to food and / or appetite level in infants fed with Infant formula that does not comprise an ingredient fermented by lactic acid producing bacteria, and 0.05 to 1.5% by weight of lactic acid based on dry weight and improved feeding behavior is determined using the Infant Feeding Behavior Questionnaire (BEBQ).

[0012] By definition, the words "non-therapeutic" exclude any therapeutic effect.

[0013] In the context of the present invention, the nutritional composition is not human milk.

Fermented ingredient

[0014] The nutritional composition in the methods or uses according to the present invention, hereinafter also referred to as the present nutritional composition, comprises a fermented ingredient. The presence of the fermented ingredient in the nutritional composition improves feeding behavior and / or self-regulation of energy intake in infants. Therefore, the presence of the fermented ingredient in the nutritional composition reduces the risk of the development of overweight or obesity.

[0015] The fermented ingredient is a composition that is fermented by lactic acid producing bacteria. Fermentation preferably takes place during the production process of the nutritional composition. Preferably, the nutritional composition does not contain significant amounts of viable bacteria in the final product due to heat inactivation after fermentation or inactivation by other means. Preferably the fermented ingredient is a product derived from milk, which is a milk substrate that is fermented by lactic acid producing bacteria, and said milk substrate comprises at least one selected from the group consisting of milk, whey, protein of whey, whey protein hydrolyzate, casein, casein hydrolyzate and lactose or derivative mixtures. Suitably, nutritional compositions comprising a fermented ingredient and non-digestible oligosaccharides and their mode of production are described in WO 2009/151330, WO 2009/151331 and WO 2013/187764.

The fermented ingredient preferably comprises fragments of bacterial cells such as glycoproteins, glycolipids, peptidoglycan, lipoteichoic acid (LTA), lipoproteins, nucleotides and / or capsular polysaccharides. Furthermore, upon fermentation and / or other interactions of the lactic acid producing bacteria with the milk substrate, additional bioactive compounds are formed, such as bioactive peptides and / or oligosaccharides and organic acids. In addition, the fermented preparation improves the efficiency of protein digestion. Therefore, the fermented ingredient, in particular the fermented milk product, is believed to have an improved effect compared to the non-fermented ingredient, in particular the non-fermented milk product.

[0017] Preferably, the nutritional composition comprises 5 to 97.5% by weight of the fermented ingredient based on dry weight, more preferably 10 to 95% by weight, more preferably 20 to 90% by weight, even more preferably 25 to 60% by weight. As a way of specifying the extent of fermentation, the level of the sum of lactic acid and lactate in the nutritional composition can be taken, since this is the metabolic end product produced by lactic acid producing bacteria after fermentation. The present nutritional composition comprises from 0.05 to 1.5% by weight of the sum of lactic acid and lactate based on the dry weight of the composition, more preferably from 0.05 to 1.0% by weight. , still more preferably 0.1 to 0.75% by weight, still more preferably 0.1 to 0.6% by weight, still more preferably 0.1 to 0.5% by weight. Preferably at least 50% by weight, still more preferably at least 90% by weight, of the sum of lactic acid and lactate is in the form of the L (+) isomer. Thus, in one embodiment, the sum of L (+) - lactic acid and L (+) - lactate is more than 50% by weight, more preferably more than 90% by weight, based on the sum of acid total lactic acid and lactate. Herein, L (+) - lactate and L (+) - lactic acid are also referred to as L-lactate and L-lactic acid.

Lactic acid producing bacteria used to produce the fermented ingredient

The lactic acid producing bacteria used to prepare the fermented ingredient, in particular for the fermentation of the milk substrate are preferably provided as a monoculture or a mixed culture. Lactic acid-producing bacteria consist of the genera Bifidobacterium, Lactobacillus, Carnobacterium, Enterococcus, Lactococcus, Leuconostoc, Oenococcus, Pediococcus, Streptococcus, Tetragenococcus, Vagococcus, and Weissella. Preferably, the lactic acid producing bacteria used for fermentation comprise the bacteria of the genus Bifidobacterium and / or Streptococcus .

[0019] Preferably the Streptococcus is a strain of S. thermophilus. Preferably Streptococcus develops beta-galactosidase activity in the course of substrate fermentation. The selection of a suitable strain of S. thermophilus is described in example 2 of EP 778885 and in example 1 of FR 2723960. In another preferred embodiment according to the present invention, the nutritional composition comprises 103-106 cfu of live S. thermophilus bacteria, per g dry weight of the nutritional composition, preferably the nutritional composition comprises 103-105 of live S. thermophilus bacteria per g dry weight.

The preferred strains of S. thermophilus to prepare the fermented ingredient for the purpose of the present invention have been deposited by the Compagnie Gervais Danone in the Collection Nationale de Cultures de Microorganismes (CNCM) run by the Pasteur Institute, 25 rue du Docteur Roux, Paris, France, on August 23, 1995 under registration number I-1620 and on August 25, 1994 under registration number I-1470.

[0021] Bifidobacteria are rod-shaped anaerobic gram-positive bacteria. Preferably the lactic acid producing bacteria used for fermentation comprise or are at least one bifidobacterium selected from the group consisting of B. breve, B. infantis, B. bifidum, B. catenulatum, B. adolescentis, B. thermophilum, B. gallicum, B. animalis or lactis, B. angulatum, B. pseudocatenulatum, B. thermacidophilum and B. longum, more preferably B. breve, B. infantis, B. bifidum, B. catenulatum, B. longum, more preferably B. longum and B. breve , even more preferably B. breve , more preferably B. breve selected from the group consisting of B. breve Bb-03 (Rhodia / Danisco), B. breve M-16V (Morinaga), B. breve R0070 (Instituto Rosell, Lallemand), B. breve BR03 (Probiotical), B. breve BR92 (Cell Biotech) DSM 20091, LMG 11613 and B. breve I-2219 deposited at the CNCM, Paris, France. More preferably, B. breve is B. breve M-16V (Morinaga) or B. breve I-2219, even more preferably B. breve I-2219.

More preferably, the nutritional composition comprises a fermented ingredient that is fermented by lactic acid bacteria comprising both B. breve and S. thermophilus. In one embodiment, the lactic acid bacteria fermentation is a Streptococcus thermophilus and Bifidobacterium breif fermentation. In one embodiment, the nutritional composition comprises a fermented ingredient where the lactic acid bacteria are inactivated after fermentation.

[0023] Preferably, the fermented ingredient is not fermented by Lactobacillus bulgaricus. Products fermented by L. bulgaricus are considered unsuitable for infants since, in young infants, the specific dehydrogenase that converts D-lactate to pyruvate is much less active than the dehydrogenase that converts L-lactate.

[0024] Preferably, the present nutritional composition comprises inactivated lactic acid producing bacteria and / or bacterial fragments derived from lactic acid producing bacteria obtained from more than 1x104 cfu of lactic acid producing bacteria per g based on the dry weight of the composition. final, more preferably more than 1x105 cfu, even more preferably more than 1x106 cfu. Preferably, the inactivated bacteria or bacterial fragments are obtained at less than 1x1014 cfu of lactic acid producing bacteria per g based on the dry weight of the final composition, more preferably less than 1x1013 cfu, even more preferably less than 1x1012 cfu.

Fermentation process

The milk substrate to be fermented is suitably present in an aqueous medium. The milk substrate to be fermented is preferably selected from the group consisting of milk, whey, whey protein, whey protein hydrolyzate, casein, casein hydrolyzate and lactose, and their derivative mixtures. The milk can be whole milk, semi-skimmed milk and / or skimmed milk. Preferably, the milk substrate to be fermented comprises skimmed milk. The buttermilk can be sweet buttermilk and / or sour buttermilk. Preferably, the whey is present in a concentration of 3 to 80 g dry weight per l of aqueous medium containing milk substrate, more preferably 40 to 60 g per l. Preferably, the whey protein hydrolyzate is present in 2 to 80 g dry weight per l of aqueous medium containing milk substrate, more preferably 5 to 15 g / l. Preferably, lactose is present in 5 to 50 g dry weight per l of aqueous substrate, more preferably 1 to 30 g / l. Preferably, the aqueous medium containing milk substrate comprises buffer salts to maintain the pH within a desired range. Preferably, sodium or potassium dihydrogen phosphate is used as a buffer salt, preferably at 0.5 to 5 g / l, more preferably 1.5 to 3 g per l. Preferably, the aqueous medium containing milk substrate comprises cysteine in an amount of 0.1 to 0.5 g per l of aqueous substrate, more preferably 0.2 to 0.4 g / l. The presence of cysteine results in a low redox potential of the substrate, which is advantageous for the activity of lactic acid producing bacteria, particularly bifidobacteria. Preferably, the aqueous medium containing milk substrate comprises yeast extract in an amount of 0.5 to 5 g / l of aqueous medium containing milk substrate, more preferably 1.5 to 3 g / l. Yeast extract is a rich source of enzyme cofactors and growth factors for lactic acid producing bacteria. The presence of yeast extract will increase fermentation by lactic acid producing bacteria.

[0026] Suitably, the milk substrate, in particular the aqueous medium containing the milk substrate, is pasteurized prior to the fermentation step to eliminate the presence of unwanted live bacteria. Suitably, the product is pasteurized after fermentation, to inactivate enzymes. Suitably, the enzyme inactivation takes place at 75 ° C for 3 min. Suitably, the aqueous medium containing milk substrate is homogenized before and / or the milk-derived product is homogenized after fermentation. Homogenization results in a more stable substrate and / or fermented product, especially in the presence of fat.

The inoculation density is preferably between 1x102 and 5x1010, preferably between 1x104 and 5x109 cfu of lactic acid producing bacteria / ml of aqueous medium containing milk substrate, more preferably between 1x107 and 1x109 cfu of lactic acid producing bacteria / ml of aqueous medium containing milk substrate. The final bacterial density after fermentation is preferably between 1x103 and 1x1010, more preferably between 1x104 and 1x109 CFU / ml of aqueous medium containing milk substrate.

The fermentation is preferably carried out at a temperature of about 20 ° C to 50 ° C, more preferably 30 ° C to 45 ° C, even more preferably about 37 ° C to 42 ° C. The optimum temperature for the growth and / or activity of lactic acid producing bacteria, more particularly lactobacilli and / or bifidobacteria, is between 37 ° C and 42 ° C.

The incubation is preferably carried out at a pH of 4 to 8, more preferably 6 to 7.5. This pH does not induce protein precipitation and / or an adverse taste, while, at the same time, lactic acid producing bacteria such as lactobacilli and / or bifidobacteria are capable of fermenting the milk substrate.

The incubation period preferably ranges from 10 minutes to 48 hours, preferably from 2 hours to 24 hours, more preferably from 4 hours to 12 hours. A sufficiently long period of time allows fermentation and the concomitant production of cell fragments, bioactive compounds and organic acids to take place to a large extent, while the incubation period does not have to be unnecessarily long for economic reasons.

[0031] Procedures for preparing fermented ingredients suitable for the purpose of the present invention are known per se. EP 778885 discloses in particular in Example 7 a suitable process for preparing a fermented ingredient. FR 2723960 discloses in particular in Example 6 a suitable process for preparing a fermented ingredient. Briefly, a milk substrate, preferably pasteurized, containing lactose and optionally additional macronutrients such as fats, preferably vegetable fats, casein, whey protein, vitamins and / or minerals, etc. it is concentrated, for example to 15-50% dry matter and then inoculated with S. thermophilus, for example 5% of a culture containing 106-1010 bacteria per ml. Preferably, this milk substrate comprises milk protein peptides. The temperature and duration of the fermentation are as mentioned above. Suitably after fermentation, the fermented ingredient can be pasteurized or sterilized and, for example, spray dried or lyophilized to provide a suitable form to be formulated into the final product.

[0032] A preferred method of preparing the fermented ingredient of the present invention is disclosed in WO 01/01785, more particularly in Examples 1 and 2. A preferred method of preparing the fermented product of the present invention is described in WO 2004/093899, more particularly in example 1.

Methods of inactivation and / or physical elimination of living cells

[0033] Preferably, the live lactic acid producing bacteria cells in the fermented ingredient are killed after fermentation, for example by inactivation and / or physical removal. Preferably the cells are inactivated. Preferably the cells are treated to render them non-replicative. Preferably the lactic acid producing bacteria are killed by heat after fermentation of the milk substrate. Preferable ways of heat killing are pasteurization (rapid), sterilization, ultra-high temperature treatment, high-temperature / short-time heat treatment, and / or spray drying at temperatures at which bacteria do not survive or no longer survive. they are not able to replicate. Cell fragments are preferably obtained by heat treatment. With this heat treatment preferably at least 90% of the living microorganisms are inactivated, more preferably at least 95%, still more preferably at least 99%. Preferably, the fermented nutritional composition comprises less than 1x105 colony forming units (cfu) of live lactic acid bacteria per g dry weight, more preferably less than 1x104, even more preferably less than 1x103 cfu of live lactic acid bacteria per g dry weight. The heat treatment is preferably carried out at a temperature ranging from 70 to 180 ° C, preferably from 80 to 150 ° C, preferably for about 3 minutes to 2 hours, preferably in the range from 80 to 140 ° C for 5 minutes to 40 minutes. Inactivation of the lactic acid bacteria advantageously results in less subsequent acidification and a safer product. This is especially advantageous when the nutritional composition is to be administered to infants or young children. Suitably after fermentation, the fermented ingredient can be pasteurized or sterilized and, for example, spray dried or lyophilized to provide a suitable form to be formulated into the final product.

Indigestible oligosaccharide

The present nutritional composition comprises a nondigestible oligosaccharide and preferably comprises at least two different nondigestible oligosaccharides, in particular two different sources of nondigestible oligosaccharides. The presence of an indigestible oligosaccharide helps promote improved eating behavior or self-regulation of energy intake. The presence of indigestible oligosaccharides beneficially affects the intestinal microbiota and makes it more similar to the intestinal microbiota of infants breastfed. This microbiota is associated with a lower risk of obesity. The combination of a fermented ingredient and indigestible oligosaccharides will further enhance the claimed benefits of the invention.

The term "oligosaccharide" as used herein refers to saccharides with a degree of polymerization (DP) of 2 to 250, preferably a DP of 2 to 100, more preferably 2 to 60, even more preferably of 2 to 10. If an oligosaccharide with a GP of 2 to 100 is included in the present nutritional composition, this results in compositions that may contain oligosaccharides with a GP of 2 to 5, a GP of 50 to 70 and a GP of 7 to 60. The term "nondigestible oligosaccharide" as used in the present invention refers to oligosaccharides that are not digested in the intestine by the action of digestive acids or enzymes present in the human upper digestive tract, for example the small intestine and the stomach, but are preferably fermented by the human gut microbiota. For example, sucrose, lactose, maltose, and maltodextrins are considered digestible.

[0036] Preferably the present nondigestible oligosaccharide is soluble. The term "soluble" as used herein, when referring to a polysaccharide, a fiber or an oligosaccharide, means that the substance is at least soluble according to the method described by L. Prosky et al., J. Assoc. Off. Anal. Chem. 71, 1017-1023 (1988).

[0037] The nondigestible oligosaccharide included in the present nutritional compositions in the methods or uses according to the present invention preferably include a mixture of nondigestible oligosaccharides. The nondigestible oligosaccharide is preferably selected from the group consisting of fructo-oligosaccharide, such as inulin, nondigestible dextrins, galacto-oligosaccharide, such as transgalacto-oligosaccharide, xyl-oligosaccharide, arabinooligosaccharide, arabinogalacto-oligosaccharide, glyco-oligosaccharide, gluco-oligosaccharide, -oligosaccharide, glucomannan-oligosaccharide, galactomannan-oligosaccharide, mannan-oligosaccharide, isomalto-oligosaccharide, nigero-oligosaccharide, glucomannan-oligosaccharide, chito-oligosaccharide, soy oligosaccharide, oligosaccharide of 3-tally uronic acid, siallyl-3 SL), 6-sialyl-lactose (6-SL), lactosialyltetrasaccharide a, b, c (LST), disialyl-lacto-N-tetrose (DSLNT), sialyl-lacto-N-hexose (S-NHL), DS- NHL, and fuco-oligosaccharide, such as fucoidan oligosaccharide (not) sulfated, 2'-fucosyl-lactose (2'-FL), 3-fucosyl-lactose (3-FL), difucosyl-lactose, lacto-N-fucopentose (LNFP) I, II, III, V, lacto-N-neofucopentose (LNnFP), lacto-N-difucosyl-hexose (LNDH) , and their derived mixtures, still more preferably selected from the group consisting of fructo-oligosaccharide, such as inulin, galacto-oligosaccharide, such as a transgalacto-oligosaccharide, and fuco-oligosaccharide and their derived mixtures, even more preferably transgalacto- oligosaccharide and / or inulin, more preferably transgalactooligosaccharide. In one embodiment in the composition or methods according to the present invention, the nondigestible oligosaccharide is selected from the group consisting of transgalacto-oligosaccharide, fructo-oligosaccharide, and derived mixtures.

[0038] The nondigestible oligosaccharide is preferably selected from the group consisting of p-galactooligosaccharide, α-galacto-oligosaccharide and galactan. According to a more preferred embodiment, the nondigestible oligosaccharide is p-galacto-oligosaccharide. Preferably, the nondigestible oligosaccharide comprises galactooligosaccharide with P (1,4), P (1,3) and / or p (1,6) glycosidic linkages and a terminal glucose. A transgalactooligosaccharide is available, for example, under the trade name Vivinal®GOS (Domo FrieslandCampina Ingredients), Bi2muno (Clasado), Cup-oligo (Nissin Sugar) and Oligomate55 (Yakult).

[0039] The nondigestible oligosaccharide preferably comprises a fructo-oligosaccharide. A fructo-oligosaccharide may, in another context, have names such as fructopolysaccharide, oligofructose, polyfructose, polyfructan, inulin, levan, and fructan and may refer to oligosaccharides comprising p-linked fructose units, which are preferably linked via P-glycosidic bonds (2 , 1) and / or P (2,6), and a preferred GP between 2 and 200. Preferably, the fructo-oligosaccharide contains a terminal glucose with P (2,1) glycosidic linkage. Preferably, the fructo-oligosaccharide contains at least 7 p-linked fructose units. In another preferred embodiment, inulin is used. Inulin is a type of fructo-oligosaccharide where at least 75% of the glycosidic bonds are P (2,1) bonds. Typically, inulin has an average chain length between 8 and 60 monosaccharide units. A suitable fructo-oligosaccharide for use in the compositions of the present invention is commercially available under the trade name Raftiline®HP (Orafti). Other suitable sources are Raftilose (Orafti), Fibrulose and Fibruline (Cosucra) and Frutafit and Frutalose (Sensus).

[0040] Preferably, the present nutritional composition comprises a mixture of galacto-oligosaccharide and fructo-oligosaccharide. Preferably, the mixture of galacto-oligosaccharide and fructo-oligosaccharide is present in a weight ratio of 1/99 to 99/1, more preferably 1/19 to 19/1, more preferably 1/1 to 19/1, more preferably from 2/1 to 15/1, more preferably from 5/1 to 12/1, even more preferably from 8/1 to 10/1, still more preferably in a ratio of about 9/1. This weight ratio is particularly advantageous when the galacto-oligosaccharide has a low medium GP and the fructo-oligosaccharide has a relatively high GP. More preferred is a mixture of galacto-oligosaccharide with an average GP below 10, preferably below 6, and a fructo-oligosaccharide with an average GP above 7, preferably above 11, even more preferably above 20. Such a mixture synergistically improves the gut microbiota.

[0041] Preferably, the present nutritional composition comprises a mixture of short-chain fructo-oligosaccharide and long-chain fructo-oligosaccharide. Preferably, the mixture of short-chain fructo-oligosaccharide and long-chain fructo-oligosaccharide is present in a weight ratio of 1/99 to 99/1, more preferably 1/19 to 19/1, even more preferably 1 / 10 to 19/1, more preferably 1/5 to 15/1, more preferably 1/1 to 10/1. A mixture of short chain fructo-oligosaccharide with an average GP below 10, preferably below 6, and a fructo-oligosaccharide with an average GP above 7, preferably above 11, even more preferably above is preferred. above 20.

[0042] The present nutritional composition comprises 0.25 to 20% by weight of total nondigestible oligosaccharide, preferably 2.5 to 20% by weight, more preferably 2.5 to 15% by weight, still more preferably 3.0 to 10% by weight, more preferably 5.0 to 7.5% by weight, based on the dry weight of the nutritional composition. Based on 100 ml, the present nutritional composition preferably comprises 0.35 to 2.5% by weight of total nondigestible oligosaccharide, more preferably 0.35 to 2.0% by weight, even more preferably of 0.4 to 1.5% by weight, based on 100 ml of the nutritional composition. A lower amount of indigestible oligosaccharide will be less effective in promoting improved eating behavior or in improving the gut microbiota, while too high an amount will lead to side effects of bloating and abdominal discomfort.

Infant formula and follow-on formula

[0043] The nutritional composition to be administered in the method according to the present invention is selected from an infant formula. This means that the present nutritional composition is not human milk. Alternatively, the term "prepared" means that it refers to a composition that is artificially prepared or, in other words, that is synthetic. Therefore, in one embodiment, the nutritional composition is selected from an artificial infant formula and an artificial follow-on formula or a synthetic infant formula and a synthetic follow-on formula. In the present context, infant formula refers to artificially prepared nutritional compositions intended for infants from 0 to about 4 to 6 months of age and intended to be a substitute for human milk. Infant formulas are typically suitable for use as the sole food source. Such preparations are also known as starter preparations. Infant formulas from 4 to 6 months of age to 12 months of age are intended to be supplementary foods for infants who are beginning to be weaned with other foods. Such preparations are also known as follow-on formulas. Infant and follow-on formulas are subject to strict regulations, for example EU commission directive 2006/141 / EC.

[0044] The nutritional composition comprises 3 to 7 g of lipids / 100 kcal, preferably 4 to 6 g of lipids / 100 kcal, more preferably 4.5 to 5.5 g of lipids / 100 kcal, of 1, 25 to 5 g protein / 100 kcal, preferably 1.25 to 4 g protein / 100 kcal, more preferably 1.25 to 3 g protein / 100 kcal, more preferably 1.25 to 2.5 g protein / 100 kcal, more preferably 1.25 to 2.25 g / 100 kcal, even more preferably 1.25 to 2.1 g protein / 100 kcal, even more preferably 1.6 to 2.0 g protein / 100 kcal, even more preferably 1.7 to 2.0 g protein / 100 kcal, even more preferably 1.75 to 1.95 g protein / 100 kcal and 6 to 16 g carbohydrate digestible / 100 kcal, preferably 8 to 16 g digestible carbohydrate / 100 kcal, more preferably 10 to 15 g digestible carbohydrate / 100 kcal.

Lipid

[0045] Herein, LA refers to acyl chain and / or linoleic acid (18: 2 n6); ALA refers to acyl chain and / or α-linolenic acid (18: 3 n3); PUFA refers to acyl chains and / or polyunsaturated fatty acids; MUFA refers to acyl chains and / or monounsaturated fatty acids; LC-PUFA refers to long chain polyunsaturated fatty acid and / or acyl chains comprising at least 20 carbon atoms in the fatty acyl chain and with 2 or more unsaturated bonds; DHA refers to acyl chain and / or docosahexaenoic acid (22: 6, n3); EPA refers to acyl chain and / or eicosapentaenoic acid (20: 5 n3); ARA refers to acyl and / or arachidonic acid chain (20: 4 n6); DPA refers to acyl chain and / or docosapentaenoic acid (22: 5 n3). PA refers to acyl and / or palmitic acid chains (C16: 0). Medium chain fatty acids (MCFA) refer to acyl chains and / or fatty acids with a chain length of 6, 8 or 10 carbon atoms.

[0046] The lipid in the nutritional composition to be administered in the method or use according to the present invention preferably comprises plant lipids. The lipid which is present in the nutritional composition in the method or use according to the invention preferably comprises PUFA, more preferably LC-PUFA, since LC-PUFA further enhance infant development. The nutritional composition preferably comprises 5 to 35% by weight of PUFA, more preferably 10 to 30% by weight of PUFA, more preferably 15 to 20% by weight of PUFA, based on total lipid. In one embodiment, the lipid in the nutritional composition for the method or use according to the invention comprises at least 10% by weight of polyunsaturated fatty acid based on total fatty acids. It is also preferred that the nutritional composition comprises MUFA, preferably 10 to 80% by weight MUFA, more preferably a 20 to 70 % by weight MUFA, more preferably 35 to 55 % by weight MUFA, based on total lipid.

[0047] LA is preferably present in an amount sufficient to promote healthy growth and development, but in as low an amount as possible to avoid the occurrence of imbalances in body growth or development. Therefore, the nutritional composition preferably comprises less than 20% by weight of LA based on total lipid, preferably 5 to 16% by weight, more preferably 10 to 14.5% by weight. Preferably, the nutritional composition comprises at least 5% by weight of LA based on total lipid. Per 100 kcal, the nutritional composition preferably comprises 350-1400 mg of LA. Preferably, ALA is present in an amount sufficient to promote healthy growth and development of the infant. Therefore, the nutritional composition preferably comprises at least 1.0% by weight of ALA based on total lipid. Preferably the nutritional composition comprises at least 1.5% by weight of ALA based on total lipid, more preferably at least 2.0% by weight. Preferably, the nutritional composition comprises less than 12.5% by weight of ALA, more preferably less than 10.0% by weight, more preferably less than 5.0% by weight. Preferably, the nutritional composition comprises a LA / ALA weight ratio of 2 to 20, more preferably 3 to 16, more preferably 4 to 14, more preferably 5 to 12.

According to the present invention, the nutritional composition preferably comprises an LC-PUFA, more preferably an LC-PUFA n-3, since an LC-PUFA n-3 promotes advantageous growth. More preferably, the nutritional composition comprises EPA, DPA and / or DHA, even more preferably d Ha. Since a low concentration of DHA, DPA and / or EPA is already effective and normal growth and development are important, the content of an LC-PUFA n-3 in the nutritional composition preferably does not exceed 15% by weight of the total fatty acid content, preferably does not exceed 10% by weight, even more preferably does not exceed 5% by weight. Preferably, the nutritional composition comprises at least 0.15% by weight, preferably at least 0.35% by weight, more preferably at least 0.75% by weight, of an LC-PUFA n-3, based on the fatty acid content. The content of DHA in the nutritional composition preferably does not exceed 10% by weight of the total fatty acid content, preferably it does not exceed 5% by weight. Preferably, the nutritional composition comprises at least 0.15% by weight, preferably at least 0.35% by weight,% by weight of DHA based on total fatty acids.

As the group of fatty acids n-6, especially arachidonic acid (ARA) and LA as its precursor, it counteracts the group of fatty acids n-3, especially DHA and EPA and a La as its precursor , the nutritional composition comprises relatively low amounts of ARA. The content of LC-PUFA n-6, more preferably ARA, preferably does not exceed 5% by weight, more preferably does not exceed 2.0% by weight, more preferably does not exceed 0.75% by weight, even more preferably it does not exceed 0.5% by weight, based on total fatty acids. The ARA may also be absent.

Protein

[0050] The nutritional composition comprises proteins in the amounts of 1.25 to 5 g of protein / 100 kcal, preferably 1.25 to 4 g of protein / 100 kcal, more preferably 1.25 to 3 g of protein / 100 kcal, more preferably 1.25 to 2.5 g protein / 100 kcal, more preferably 1.25 to 2.25 g / 100 kcal, even more preferably 1.25 to 2.1 g protein / 100 kcal, even more preferably 1.6 to 2.1 g protein / 100 kcal, still more preferably 1.6 to 2.0 g protein / 100 kcal, even more preferably 1.7 to 2.0 g protein / 100 kcal, even more preferably 1.75 to 1.95 g protein / 100 kcal. An optimal amount of protein will beneficially affect eating behavior. The combination of a fermented ingredient and the optimal amount of protein has a further improved effect on eating behavior and / or self-regulation of energy intake. The protein source should be selected so that the minimum requirements for essential amino acid content are met and satisfactory growth is ensured. Therefore, protein sources based on cow's milk proteins such as whey, casein and their derived mixtures and proteins based on soy, potato or pea are preferred. In the case where whey proteins are used, the protein source is preferably based on acid whey or sweet whey, whey protein isolate or derivative mixtures and may include α-lactalbumin and P-lactoglobulin. More preferably, the protein source is based on acid whey or sweet whey from which caseino-gluco-macropeptide (CGMP) has been removed. Preferably, the composition comprises at least 3% by weight of casein based on dry weight. Preferably the casein is intact and / or not hydrolyzed. For the present invention, the protein includes free peptides and amino acids.

Digestible carbohydrates

The nutritional composition comprises digestible carbohydrate in the amounts specified above. Preferred digestible carbohydrate sources are lactose, glucose, sucrose, fructose, galactose, maltose, starch, and maltodextrin. Lactose is the main digestible carbohydrate present in human milk. Lactose advantageously has a low glycemic index. The nutritional composition preferably comprises lactose. The nutritional composition preferably comprises digestible carbohydrate, where at less 35 % by weight, more preferably at least 50 % by weight, more preferably at least 75 % by weight, even more preferably at least 90% by weight, more preferably at least 95% by weight of the digestible carbohydrate it is lactose. Based on dry weight, the present composition preferably comprises at least 25% by weight of lactose, preferably at least 40% by weight.

App

[0052] In the method or use according to the present invention, a nutritional composition is administered to an infant or used in an infant. In the context of the present invention, an infant is up to 12 months old. Preferably, the nutritional composition is administered to or used in a full-term infant. A term infant means an infant born with a gestational age of> 37 to <42 weeks. Preferably, the nutritional composition is administered to or used in a healthy infant. Preferably, the nutritional composition is used at least during the first 2 months of life, preferably at least during the first 3 months of life of the infant, more preferably at least during the first 4 months of life of the infant. The nutritional composition is administered to an infant below 6 months of age, more preferably below 4 months of age.

[0053] In one embodiment the present invention is particularly suitable later in life for infants raised in an obesogenic environment, or following the Western diet.

[0054] An obesogenic environment, or obesogenic diet, or western type diet is high in calories, high in fat and high in sugar. Fat is high in saturated fat, has a high ratio of n6 / n3 fatty acids, and is high in cholesterol. The diet is generally characterized by a high intake of processed meat, red meat, butter, many fatty dairy products, sugar, and refined grains. The WHO / FAO has guidelines for the recommended diet and the Western-type diet is deviating from these guidelines, Food and Nutrition Paper 91: Fats and fatty acids in human nutrition - Report of an expert consultation of FAO (United Nations United Nations Food and Agriculture Organization), which took place on 10-14 November 2008 in Geneva, available in print in November 2010, ISBN 978-92-5-106733-8. The Western-type diet is sometimes also called the Standard American Diet. For the purposes of the present invention, Western foods or, in other words, a Western-type diet is preferably characterized by the fact that 1) more than 30% of the total calories is provided by fat, 2) it comprises at least 10% by weight of saturated fat based on the total amount of fat, 3) comprises at least 0.5% by weight of cholesterol based on total fat, 4) the n6 / n3 ratio of fatty acids in fat dietary fat is above 4 and, in an improved definition, the n6 / n3 ratio of fatty acids in dietary fat is above 10.

Thus, according to an embodiment of the present invention, the nutritional composition is to be used in an infant who is exposed to an obesogenic environment and / or a Western-type diet later in life, preferably when the infant are over 36 months of age. Therefore, the present invention is intended in particular for children at risk of being obese later in life. Therefore, the present invention is intended in particular for children raised in an obesogenic environment. An obesogenic environment is an environment where humans are surrounded by cheap, fast, nutritionally inferior food, and a built environment that discourages physical activity.

[0056] The present invention also relates to improving infant energy intake self-regulation towards observed energy intake self-regulation in breastfed infants, preferably compared to energy intake self-regulation in breastfed infants. Infant formula that does not comprise a fermented ingredient as defined herein, or in other words that does not comprise lactic acid in the range defined herein. In a preferred embodiment, the improved eating behavior is selected from the group consisting of slower eating, greater responsiveness to satiety, decreased response to food, optimal meal enjoyment, and an optimal appetite, more preferably, a greater responsiveness to satiety, a decreased responsiveness to food and a decreased overall appetite, preferably compared to the rate of intake, responsiveness to satiety, the responsiveness to food, the level of enjoyment of the food and / or the level of appetite in infants fed with infant formula that does not comprise a fermented ingredient as defined herein, or in other words, that does not comprise lactic acid in the range defined here

[0057] The reduction of the risk of developing overweight and / or obesity and / or the prevention of overweight and / or obesity in an infant is promoted. More preferably, a reduction in the risk of developing overweight and / or obesity later in life and / or prevention of overweight and / or obesity in an infant later in life is promoted. More preferably, a reduction in the risk of childhood obesity and / or prevention of childhood obesity in an infant is promoted.

EXAMPLES

Example 1: trajectories of growth and development of body composition in the first years of life in infants consuming a partially fermented infant formula or a control formula compared to a control group of breastfed infants

[0058] The growth and safety of an experimental preparation (Preparation 1) versus a control preparation (Preparation 2) was investigated in an exploratory clinical study, using a 3-4 month intervention in healthy term infants. In a multicenter, double-blind, randomized, controlled, prospective clinical trial, infants were enrolled before 28 days of age and assigned to receive one of two formulas until 17 weeks of age.

[0059] Experimental infant formula 1 is an infant formula containing 0.8 g / 100 ml of non-digestible oligosaccharides of scGOS (Vivinal® GOS source) and lcFOS (RaftilinHP® source) in a weight ratio of 9: 1. Of this infant formula, 30% based on dry weight was derived from Lactofidus ™, a commercially available infant formula marketed under the brand name Gallia. Lactofidus ™ is a composition derived from fermented milk and is produced by fermenting with S. thermophilus and comprises B. breve. A mild heat treatment is employed. Infant formula 1 comprised about 0.33% by weight of lactic acid lactate based on dry weight, of which at least 95% is L-lactic acid L-lactate. Control Infant Formula 2 is an unfermented infant formula without scGOS / lcFOS. The composition of the two preparations was similar in energy and macronutrient composition (per 100 ml: 66 kcal, 1.2 g of protein (bovine whey protein / casein in a ratio of 1/1 by weight), 7.7 g of digestible carbohydrate (of which 7.6 g are lactose), 3.4 g of fat (mainly vegetable fat). The composition also included vitamins, minerals, trace elements and other micronutrients according to the international directive 2006/141 / EC for an infant formula.

[0060] As a reference, a group of infants who were exclusively breastfed until 17 weeks of age was included. The intention-to-treat (ITT) population consisted of all subjects randomized to infant formula (n = 199), in addition 100 subjects were included in the breastfed control group. The ITT population consisted of 94 subjects in the experimental group, 105 subjects in the control group. The per protocol population (PP) consisted of all subjects in the ITT group with no deviations from the predetermined protocol. For growth data analysis, PP analysis was considered the primary (main) analysis, this population consisted of 145 randomized subjects (71 in the experimental group and 74 in the control group) and 86 breastfed subjects. A total of 75 subjects terminated the study prematurely, n = 22 for the experimental group, n = 25 for the control group (no significant difference between groups), and n = 28 in the breastfed control group. The reasons for early termination were subjects with an adverse event (n = 5 for experimental, n = 9 for control, n = 0 for breastfed), withdrawal of consent (n = 2 for experimental, n = 3 for control, n = 17 for breastfed), lost to follow-up (n = 4 for experimental, n = 1 for control, n = 7 for breastfed) and others (n = 11 for experimental, n = 11 for the control, n = 4 for the breastfed). There was no difference between the experimental and control groups with respect to baseline characteristics, except that there were more twins in the control group. There was no difference between the experimental and control groups with respect to parental characteristics.

[0061] Growth was evaluated by equivalence analysis of daily weight gain during the intervention period using equivalence margins of ± 0.5 SD, between the preparation groups (per protocol) as compared to the group breastfed referral. In addition, the increase in length was also monitored on a monthly basis. A parametric growth curve (PGC) model was used to test the equivalence of weight gain in the different treatment arms. In addition to the PGC (parametric growth curve) model, GLM (generalized linear model (ANCOVA)) and AMN (arbitrary means model) were used to control the correctness of the model. ANCOVA and AMN generated similar results to the PGC, indicating the validity of the PGC model.

Results

[0062] Weight gain per day (grams / day) was calculated as "difference in weight" divided by "difference in elapsed time" to test for superiority. Table 1 shows the weight gain (g / day) throughout the study period (from baseline to week 17). Comparisons with the breastfed control group led to statistically significant differences for control group 2, as a result of the greater weight gain in the control group, (p value of control vs. breastfed 0.028). There was no statistically significant difference over time for infants fed Experimental Formula 1 compared to infants fed Control Formula 2, or the control breastfed group. The results for the ITT population were in line with the results for the PP population.

[0063] Table 2 presents the results of the PGC model with contrast estimates for the difference in weight gain (grams / day) between the study groups for the PP population. The equivalence in weight gain between experimental group 1 and the breastfed reference group was confirmed (CI: -0.5161 to 3.0293 and estimate 1.2566) (p = 0.2432), but, for the control group 2, no equivalence was demonstrated with those who were breastfed (CI: 0.7619 to 4.0966 and estimate 2.4292) (p = 0.0168), with a greater weight gain in control group 1. When the 2 groups of preparations are compared, the 90% confidence intervals of the estimated difference (CI: -2.9260 to 0.6442 and estimate -1.1409) were completely between -0.5 * SD and 0, 5 * SD (margin of equivalence), which means that all comparisons confirmed equivalence in weight gain (g / day) between experimental group 1 and control group 2 (p = 0.2926). The results for the ITT population were in line with the results for the PP population.

Table 2: Contrast Estimates for Difference in Weight Gain (grams / day) Between PP and ITT Study Groups

[0064] No statistically significant difference in length increase was observed between experimental preparation group 1, control preparation group 2 and the breastfed control group, for the PP group, as well as for the ITT group.

[0065] When analyzing the increase in body mass index (BMI) per day (kg / m2 / day) it was calculated as the "difference in BMI" divided by the "difference in elapsed time" to test superiority. Table 3 shows the increase in BMI (kg / m2 / day) throughout the entire study period (from baseline to week 17). Comparisons with the breastfed control group led to statistically significant differences for control group 2, as a result of the greater increase in BMI in the control group, (p value of control vs. breastfed 0.007). There was no statistically significant difference over time for infants fed Experimental Formula 1 compared to infants fed Control Formula 2, or the control breastfed group. The results of the ITT population were in line with the results of the PP population, but additionally in the experimental group 1 the increase in reduced BMI, compared to the control preparation group 2, was statistically significant (p = 0.012).

Table 3a: increase in BMI of infants (kg / m2 / day) from baseline to week 17, (PP)

Table 3b: increase in BMI of infants (kg / m2 / day) from baseline to week 17, (ITT)

[0066] Table 4 presents the results of the PGC model with contrast estimates for the difference in BMI increase (kg / m2 / day) between the study groups for the PP-G population. The equivalence in the increase in BMI between experimental group 1 and the breastfed control group was confirmed (CI: -0.0007 to 0.0086 and estimate 0.0039) (p = 0.1639). For control group 2, no equivalence with breastfed was demonstrated (CI: 0.0012 to 0.0097 and estimate 0.0054) (p = 0.0334). When the two preparation groups were compared, the 90% confidence intervals of the estimated difference (CI: -0.0062 to 0.0028 and estimate -0.0017) were completely between -0.5 * SD and 0, 5 * SD (margin of equivalence), which means that all comparisons confirmed equivalence in the increase in BMI between experimental group 1 and control group 2 (p = 0.5292). The results for the ITT population were in line with the results for the PP population.

Table 4: Contrast Estimates for Difference in BMI Increase (kg / m2 / day) Between Study Groups, PP, and ITT

[0067] The preparation without fermented ingredient, with a protein content of 1.8 g / 100 kcal, which is considered low in the art, does not show an improved growth trajectory comparable to the reference group of breastfed as such, but in presence of fermented ingredient improves growth trajectory. These results are indicative of a trajectory of growth and development of body composition in infants consuming an infant formula that is partially fermented that is more similar to the trajectory of growth and development of body composition in breastfed infants. These results are indicative of a reduced risk of developing overweight or obesity in infants who consume at least part of the fermented infant formula.

Example 2: feeding behavior differs in infants receiving the experimental formula compared to the control formula at week 17

[0068] In the clinical study of Example 1, parents filled in questionnaires on the feeding behavior of babies (Llewellyn et al. Appetite 2011, 57: 388-96). The Infant Feeding Behavior Questionnaire (BEBQ) is a widely validated tool that has been shown to be capable of assessing feeding behavior in infants. The BEBQ generates scores on the following scales: response to food, enjoyment of food, response to satiety, slowness to eat, and general appetite. The Infant Feeding Behavior Questionnaire (BEBQ) has 18 questions with answers on a 5-point scale (never, rarely, sometimes, often, always). Items are used to calculate scores on the following scales: response to food (6 items), enjoyment of food (4 items), response to satiety (3 items), slow eating (4 items), and general appetite ( 1 element).

[0069] At the first visit (inclusion visit), as expected, no significant difference was observed between the control and experimental groups. However, when the infants were 17 weeks old, significant differences were observed, see Table 5, and also changes when compared to baseline, see Table 6. Response to satiety increased and general appetite decreased by the group that received the experimental preparation compared to the control group, while the slowness to eat increased, the response to the food decreased and the enjoyment of the food decreased, but they did not show significant differences (Wilcoxon-Mann-Whitney tests ).

When the infants were 17 weeks of age, significant differences in feeding behavior were observed when compared to the baseline. The response to satiety increased and the response to food and general appetite decreased in the group that received the experimental preparation. Slow eating increased and enjoyment of food was lower as well, but not statistically significant.

Table 5: BEBQ Results of Infants Receiving Experimental Formula Compared to Infants Receiving Control Formula at Week 17, ITT

Table 6: BEBQ Results of Infants Receiving Experimental Formula Compared to Infants Receiving Control Formula at Week 17, Change from Baseline, ITT Group

[0070] As shown in Llewellyn et al. (Appetite 2011, 57: 388-96), Mallan et al. (Apetite, 2014; 82: 43-49) and Jaarsveld et al. (JAMA Pediatr 2014, 168 (4): 345-350) all the changes observed in eating behavior in the experimental group, even if they do not become significant, are indicative of a lower risk of developing overweight or obesity later in life. life.

[0071] The data on the intake of the preparation also suggest a correlation between eating behavior, in particular the response to satiety and general appetite, and the intake of the preparation. Without wishing to be bound by theory, the lower weight gain and BMI growth trajectories observed in the experimental group, which are closer to the growth trajectories of the breastfed reference group, could be explained by a better self-regulation of energy intake due to improved feeding behavior.

[0072] Both the observed effect on eating behavior and growth trajectories, which are more similar to the breastfed control group, indicate a lower risk of developing overweight or obesity later in life for infants who consume an infant formula ( partially) fermented.

Example 3: trajectories of growth and development of body composition in the first years of life in infants consuming an infant formula comprising a partially fermented preparation, comprising indigestible oligosaccharides, or comprising both

[0073] The following data are shown to demonstrate that the effect on the growth path is mainly due to the presence of a partially fermented preparation and that the presence of non-digestible oligosaccharides has less effect.

A clinical trial similar to that described in Example 1 was conducted. In a multicenter, double-blind, prospective, randomized clinical trial, infants were enrolled before 28 days of age and assigned to 3 test groups to receive one of three formulations:

Test group 1, infant formula 1 partially fermented with indigestible oligosaccharides (50F +): where infant formula 1 comprises per 100 ml 66 kcal, 1.35 g of protein (bovine whey protein / casein in proportion in weight 1/1), 8.2 g digestible carbohydrate (of which 5.6 g are lactose and 2.1 g, maltodextrin), 3.0 g fat (mainly vegetable fat), 0.8 g oligosaccharides nondigestibles comprising scGOS (Vivinal® GOS source) and lcFOS (RaftilinHP® source) in a weight ratio of 9: 1. Of this infant formula, approximately 50% by weight based on dry weight is derived from Lactofidus ™. The infant formula comprises about 0.55% by weight lactic acid lactate based on dry weight, of which at least 95% is L (+) - lactic acid / lactate. The composition also comprises vitamins, minerals, trace elements and other micronutrients according to the international directive 2006/141 / EC for an infant formula.

Test Group 2: Partially fermented infant formula 2 without indigestible oligosaccharides, (50F-) similar to infant formula 1 but without the indigestible oligosaccharides scGOS and lcFOS. Test Group 3: Infant Formula 3 (0F +), an unfermented infant formula containing 0.8 g of indigestible oligosaccharides comprising scGOS (Vivinal® GOS source) and lcFOS (RaftilinHP® source) in a weight ratio of 9: 1, and for the rest similar in composition to infant formula 1.

[0074] In statistical analyzes, comparisons of interest were investigated. The effect of the fermented preparation was evaluated by comparison of test groups 3 (0F +) and 1 (50F +). The effect of the addition of nondigestible oligosaccharide was evaluated by comparison of test groups 3 (50F +) and 2 (50F).

[0075] Of the total of 432 randomized subjects, 16 subjects were excluded from the All Subjects Treated (AST) population as they did not consume any study product. One subject was diagnosed with hypothyroidism and was considered unhealthy, wrongly randomized, and excluded from the ITT analysis. A total of 276 subjects completed the study until 17 weeks of age, while 155 (36%) of the subjects left the study prematurely. Apparently, the number of subjects who completed the study was not different between the groups. There was no difference in the reasons for dropping out between the groups. The population per protocol was 79, 65 and 74 subjects for groups 1,2 and 3, respectively. At baseline, no difference was observed in the subject characteristics, including sex ratio, of the PP intervention groups, except for a higher number of first-born infants in group 1 versus group 2, which is considered statistically significant, different by chance and without clinical relevance. Anthropometric measures at baseline were not statistically different between treatment groups.

Results

The mean weight gain (gram / day) in the PP population at week 17 was maximum in test group 3 with indigestible oligosaccharides but no fermented ingredient and minimum in test group 2 with fermented ingredient but no indigestible oligosaccharides. Median weight gain showed a similar pattern. The mean length increase (mm / day), on the other hand, was quite similar in groups 2 and 3, but greater in group 1, see table 7.

Table 7: Increase in weight (gram / day) and length (mm / day) per preparation from study entry to 17 weeks of age for the per protocol group.

[0077] Using PGC (parametric growth curve) analysis similar to example 1, the estimated difference in weight gain in group 3 (0F +) versus group 1 (50F +) was 0.15 and the increase in length was -0.05. In other words, in the group that consumed the preparation with the fermented ingredient, the weight gain was lower than in the group that consumed a preparation without the fermented ingredient, while the increase in length in both groups was similar. Nondigestible oligosaccharides were present in both preparations.

[0078] Also, the estimated difference in weight gain in group 2 (50F vs. 50F +) versus group 1 was -0.31 and the length gain was -0.03. In other words, in the group that consumed the preparation with the fermented ingredient, but without indigestible oligosaccharides, the weight gain was lower than in the group that consumed a preparation with the fermented ingredient with indigestible oligosaccharides and the increase in length in both groups was similar.

In the same study, one group received the same preparation as test group 1 with the only difference that instead of 50% by weight it contained 15% by weight of Lactofidus ™ based on the dry weight of the composition. The results on the growth path for the 15% by weight of the fermented ingredient were even more advantageous than the 50% by weight which showed the beneficial effect in a wide range.

[0079] These effects on weight and length gain are indicative of a lower weight gain per length and a lower increase in BMI mainly due to the consumption of a partially fermented preparation and not, or to a lesser extent, due to the consumption of a preparation with indigestible oligosaccharides. These results show that the beneficial effect on the body growth and development trajectory is mainly caused by the presence of a partially fermented infant formula, and not by the presence of indigestible oligosaccharides. In this clinical study, no breastfed control group or control group with no fermented ingredient and no indigestible oligosaccharides were included, so conclusions can only be drawn about the effect of a fermented ingredient that reduces weight gain and reduces weight gain. increased BMI, while the presence of indigestible oligosaccharides has no or less effect.

Claims (11)

1. Non-therapeutic method to promote improved self-regulation of energy intake in an infant, wherein said method comprises administering a nutritional composition that is an infant formula comprising 3 to 7 g of lipids / 100 kcal, of 1.25 to 5 g of protein / 100 kcal and 6 to 16 g of digestible carbohydrate / 100 kcal and where the nutritional composition comprises an ingredient fermented by lactic acid producing bacteria, and from 0.05 to 1.5% by weight of lactic acid based on the dry weight and where the nutritional composition comprises from 0.25% by weight to 20% by weight of indigestible oligosaccharides based on the dry weight of the nutritional composition, where the nutritional composition is administered at a infant with an age below 6 months, more preferably below 4 months of age and the improved self-regulation of energy intake is compared with the self-regulation of energy intake of infants fed pr Infant preparation that does not comprise an ingredient fermented by lactic acid producing bacteria, and 0.05 to 1.5% by weight of lactic acid based on dry weight. 2. Non-therapeutic method to promote improved feeding behavior in an infant, where improved feeding behavior is selected from the group consisting of slower eating, more responsive to satiety, less responsive to food , optimal food enjoyment and optimal appetite, more preferably increased responsiveness to satiety, decreased response to food, and decreased overall appetite, wherein said method comprises administering a nutritional composition that is an infant formula comprising 3 to 7 g of lipids / 100 kcal, 1.25 to 5 g of protein / 100 kcal and 6 to 16 g of digestible carbohydrate / 100 kcal and where the nutritional composition comprises an ingredient fermented by lactic acid producing bacteria, and from 0.05 to 1.5% by weight of lactic acid based on dry weight and where the nutritional composition comprises 0.25% by weight to 20% by weight of nondigestible oligosaccharides based on the dry weight of the nutritional composition, where the nutritional composition is administered to an infant below 6 months of age, more preferably below 4 months of age. age, and improved feeding behavior is compared to feeding rate, satiety responsiveness, food responsiveness, and / or appetite level in infants fed a formula that does not contain an ingredient fermented by lactic acid producing bacteria, and 0.05 to 1.5% by weight of lactic acid based on dry weight and improved feeding behavior is determined using the Infant Feeding Behavior Questionnaire (BEBQ). 3. Non-therapeutic method according to claim 1 or 2, wherein the nutritional composition comprises 1.6 to 2.1 g of protein / 100 kcal Non-therapeutic method according to any one of the preceding claims, wherein the indigestible oligosaccharides are selected from the group consisting of fructo-oligosaccharides and galacto-oligosaccharides. Non-therapeutic method according to any of the preceding claims, wherein the lactic acid producing bacteria are Bifidobacterium breve and / or Streptococcus thermophilus. Non-therapeutic method according to any of the preceding claims, wherein the nutritional composition comprises inactivated lactic acid producing bacteria. 7. Non-therapeutic method according to any of the preceding claims, wherein the nutritional composition comprises 1.7 to 2.0 g of protein / 100 kcal. 8. Non-therapeutic method according to any of the preceding claims, wherein the nutritional composition comprises 1.75 to 1.95 g of protein / 100 kcal. Non-therapeutic method according to any one of the preceding claims, wherein the nutritional composition comprises lactic acid and lactate in an amount of 0.1 to 0.75% by weight based on the dry weight of the composition. Non-therapeutic method according to any of the preceding claims, wherein the nutritional composition comprises long chain n-3 polyunsaturated fatty acids (LC-PUFA) in an amount not exceeding 15% by weight of the total fatty acid content, and which is at least 0.15% by weight based on the fatty acid content. Non-therapeutic method according to any one of the preceding claims, wherein the infant is exposed to an obesogenic environment and / or Western type of diet later in life.